This invention is in the field of antiviral agents and specifically relates to compounds, compositions and methods for treating Herpes Simplex Virus.
There is a great need for new therapies for the treatment of viral diseases. Whereas there has been great progress in developing a variety of therapies for the treatment of bacterial infections, there are few viable therapies for the treatment of viruses. Zidovudine is the primary approved treatment for human immunodeficiency virus. Ganciclovir, acyclovir, and foscarnet are currently utilized for the treatment of herpesvirus infections. However, these therapies can have substantial side effects based on their deleterious effects on host cell DNA replication or their effect on a limited number of viral infections. In addition, viruses are known to develop resistance to therapies, which causes a progressive decline in efficacy.
Viruses are classified into broad categories based on whether they incorporate RNA or DNA. Important virus families classified of the DNA type include adenoviridae, poxviridae, papovaviridae and herpesviridae.
Herpesviridae is a family of DNA viruses which include herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV6), human herpesvirus-7 (HHV7), human herpesvirus-8 (HHV8), pseudorabies and rhinotracheitis, among others.
It is known that herpesviruses express their genetic content by directing the synthesis of a number of proteins encoded by the herpesvirus DNA in the host cell. One of the important virus-encoded proteins is made as a precursor consisting of an amino terminal-located protease and carboxyl terminal-located assembly protein. This precursor is proteolytically processed in an autocatalytic manner at a specific amino acid sequence known as the xe2x80x9creleasexe2x80x9d site yielding separate protease and assembly protein. The assembly protein is cleaved further by the protease at another specific amino acid sequence known as the xe2x80x9cmaturationxe2x80x9d cleavage site. Recently, EP 514,830, published Nov. 25, 1992, describes a virus-specific serene protease which has a role in herpesvirus replication. Additionally, Lui and Roizman (J. Virol, 65, 5149 (1991)) describe the sequence and activity of a protease and the associated assembly protein encoded by UL26 of HSV-1. A. R. Welch et al. (Proc. Natl. Acad. Sci. USA, 88, 10792 (1991) and WO93/01291, published Jan. 21, 1993) describe the related protease (also known as assemblin) and assembly protein encoded by UL80 of CMV. An approach currently being investigated for potential use in the treatment of herpesvirus infections is the development of inhibitors of herpesvirus proteases.
4H-3,1-Benzoxazinones have been described in the literature as having serine protease activity, among others. For example, Teshima et al. (J. Biol. Chem., 257, 5085-5091 (1982)) describes various 2-alkyl-4H-3,1-benzoxazin-4-ones as enzyme inhibitors. Moorman and Abeles (J. Amer. Chem. Soc., 104, 6785-6786 (1982)) describes 4H-3,1-benzoxazin-2,4-dione as having some enzyme inhibitory activity. R. Stein, et al. (Biochemistry, 26, 4126-4130, (1987)) describes 2-alkyl-4H-benzoxazin-4-ones, with further substitution at the 5, 6 and 7 positions, as inhibiting the elastase enzyme. WO92/18488 (published Oct. 29, 1992) describes 2-alkyl-4H-3,1-benzoxazin-4-ones with substitution at the 5 and 7 positions as selective inhibitors of elastase. EP Pub. 206,323 (published Dec. 30, 1985) describes 2-alkoxy-, 2-aryloxy- and 2-aralkoxy-4H-3,1-benzoxazin-4-ones, having substitution at the 5, 6, 7 and 8 positions, as enzyme inhibitors. U.S. Pat. No. 4,745,116 to A. Kranz et al. describes 2-alkoxy, 2-aryloxy- and 2-aralkoxy-4H-3,1-benzoxazin-4-ones, having further substitution at the 5, 7 and 8 positions, as enzyme inhibitors. U.S. Pat. No. 5,428,021 to Hiebert et al. describes 6-(aminoacid)amino-2-alkoxybenzoxazinones as elastase inhibitors. WO 96/07648, published Mar. 14, 1996, describes 2-phenylamino-benzoxaziones for the treatment of Alzheimer""s, and specifically 6-chloro-2-(2-iodophenylamino)-benzo[d][1,3]oxazin-4-one is described.
2-Amino-4H-3,1-benzoxazinones have been described. A Krantz et al. (J. Med. Chem., 33, 464-479 (1990)) describes 4H-3,1-benzoxazin-4-ones substituted with alkyl, alkylamino, alkoxy and alkylthio substituents at the 2-position, and with further substitution at the 5, 6 and 7 positions, as elastase inhibitors. Uejima et al. (J. Pharm. Exp. Ther., 265, 516-522 (1993)) describe 2-alkylamino-5-methyl-7-acylamino-4H-3,1-benzoxazin-4-ones as highly selective elastase inhibitors with significant plasma stability. U.S. Pat. No. 4,657,893 to Krantz et al. describes 2-alkylamino- and 2-alkylurido-4H-3,1-benzoxazin-4-ones having further substitution at the 5,7 and 8 positions, as enzyme inhibitors.
F. L. M. Alvarez (An. Quim., 79, 115-17 (1983)) describes the preparation of 2-sulfonylamino-4H-3,1-benzoxazinones. J. G. Tercero et al. (An. Quim., 83, 247-50, (1987)) describes the preparation of 2-arylsulfonylamino-4H-3,1-benzoxazinones.
I. Butula et al. (Croat. Chem. Acta, 54, 105-8 (1981)) describe the synthesis of 2-alkylamino-4H-3,1-benzoxazinones. H. Urich et al. (J. Org. Chem., 32, 4052-53(1967)) describes the synthesis of 2-alkylamino-4H-3,1-benzoxazinones. E. Papadopoulos (J. Heterocyclic. Chem., 21, 1411-14 (1984)) describes the use of 2-haloalkylamino-4H-3,1-benzoxazin-4-one as a starting material for the synthesis of phenylureas. EP Appln. 466,944 (published Jan. 22, 1992) describes 2-alkylamino-7-acylamino-5-alkyl-4H-benzoxazin-4-ones as selective enzyme inhibitors of elastase.
M. Badawy et al. (J. Heterocyclic. Chem., 21, 1403-4 (1984)) describe the use of N-phenyl-2-amino-4H-3,1-benzoxazin-4-one as a starting material for the synthesis of quinazolines. R Khan et al. (J Chem. Research(S), 342-43(1992) describe the synthesis of 2-[5-aryl-1,3,4-oxadiazol-2-yl]amino-4H-3,1-benzoxazin-4-ones.
WO 96/37485 describes antiviral agents and compounds, compositions, and methods for treating herpes-related disorders. This document does not describe compounds that have specificity to HSV.
It was discovered that specific compounds that fall within the generic scope of Formula II of WO 96/37485 are very effective against HSV at lower concentrations than the compounds of the examples specifically disclosed in WO 96/37485. The compounds of the present invention have specificity to HSV. This specificity is deemed to be derived from structural conformation of the compounds having R28 and R29 substituents.
The present invention is directed to a compound of Formula II: 
wherein R28 is selected from amino optionally substituted with two radicals selected from alkyl, aralkyl, heterocyclylalkyl, heterocyclyl, and aryl;
wherein R29 is selected from 
wherein R30 is selected form alkyl, alkoxy, alkylamino, carboxyalkyl, alkoxylky, alkylaminoalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,aralkyl, aralkoxy, aryloxy, cycloalkyloxy, arylamino, aralkenyl, heterocyclylalkoxy, alkylaminoalkoxy, alkylaminoalkylamino, heterocyclylalkylamino, N-aryl-N-alkylamino, and N-aralkylamino; wherein R31 is alkyl; wherein R32 is selected from alkyl and aryl; and wherein R33 is selected from hydrido, halo and alkyl;
or a pharmaceutically-acceptable salt thereof.
The present invention is further directed to a pharmaceutical composition comprising a therapeutically-effective amount of a compound of formula II and a pharmaceutically acceptable carrier or diluent.
The present invention is further directed to a method or therapeutic or prophylactic treatment of Herpes Simplex Virus in a subject, said method comprising treating said subject with an effective amount of a compound of formula II.